Skeletal muscle Nr4a1 hypomethylation and gene induction reduce insulin sensitivity in sedentary maternal high-fat offspring

Maternal high-fat consumption has negative effects on the offspring’s obesity/diabetes susceptibility and we hypothesize that epigenetic modifications in the skeletal muscle are partly responsible for this phenotype. To detect genes affected by maternal nutrition, offspring of low-fat (LF) and high-fat (HF) diet fed dams (C57BL/6 mice) received LF diet upon weaning and were sacrificed at an age of 6 or 25 weeks. M. quadriceps gene expression was investigated by microarray analysis revealing upregulation of the nuclear receptor Nr4a1 by maternal HF feeding. This was accompanied by promoter hypomethylation of CpG‑1408 which correlated with higher Nr4a1 gene expression at both ages. Offspring voluntary exercise training normalized Nr4a1 methylation/expression and ameliorated the negative effects of maternal HF feeding on insulin sensitivity. Overall, Nr4a1 expression correlated with higher insulin levels during oral glucose tolerance test and could, therefore, be involved in the programming offspring’s diabetes susceptibility.